This development award will provide the candidate with the training required to address mechanisms and events associated with drug-induced pulmonary fibrosis. The investigative methods learned and applied during the five years will provide another means of pursuing his research interest in pulmonary toxicology and pharmacology. A professional development plan consisting of research, scholarship, involvement with national meetings, workshops, and professional society memberships will form the foundation of the candidate's transition to an independent investigator. RESEARCH PROJECT Lung fibrosis is the limiting toxicity of the antineoplastic drug bleomycin. Much of the current evidence implicates the alveolar macrophage (AM) as playing a central role in the development of the bleomycin-induced lung fibrosis. The overall goal of this proposal is to characterize the role of the alveolar macrophage in this process. Acute in vitro effects of bleomycin can be studied by incubating alveolar macrophages from normal volunteers with bleomycin. The interstitial fibrosis that characterizes bleomycin toxicity in humans can be reproduced with a mouse model. Therefore, these studies will use AMs from humans and inbred mouse strains together with techniques of cell physiology and cell biology. The studies will be divided into the following sections: 1) characterization of the in vitro effects of bleomycin on human and two inbred mouse strains (bleomycin-sensitive and -resistant); 2) description of the potential molecular mechanism of action of bleomcyin on the AM; and 3) determination of the role of the AM in the development of lung fibrosis using the mouse models. The longer term effects of bleomycin on the mouse AM in vivo will be examined by measuring effects of the drug on cells lavaged as a function of time after initiation of drug infusion. Measured effects in these studies will make use of in situ hybridization to determine the cytokines produced by the AM and the cytokine receptors present on the AM at various stages of the disease process. Hypotheses developed as a result of the macrophage cytokines produced at various times will be tested by infusion of cytokines and anti-cytokine antibodies to either produce or block fibrosis. The studies outlined in this proposal will lay the groundwork for a more complete understanding of the mechanisms involved in the response of lung cells to this drug, which in turn may lead to rational suggestions for pharmacologic intervention that will inhibit bleomycin-induced fibrosis while maintaining the antineoplastic properties of the drug.